alpha-phenyl(pyridyl or piperidyl)alkyl esters of (chloro or lower alkoxy)-benzoic acids and congeners



.benzyl and phenethyl' groupings.

3,100,775 Patented Aug. 13, 1963- United States Patent OffiC i 3 100 71s a-PHENYHPYRIDYI: oR PIPERIDYL)ALKYL ESTERS F (CHLORO 0R LOWER ALKOXY)- BENZOIC ACIDS AND CONGENERS Kurt J. Rorig, Glenview, 111., assignor to G. D. Sear le &

(10., Chicago, 111., a corporation of Delaware N0 Drawing. Filed Apr. 1, 1959,-Ser. No. 803,371

16 Claims. (Cl. 260-295) This invention relates to aryl(cyclic amino) alkyl esters of substituted aromatic acids, and to processes for the manufacture thereof. More particularly, this invention relates to compounds of the formula wherein Het designates a nitrogenous heterocyclic radical optionally alk'ylated, aralkylated, or N-oxygenated; Ar designates hydrogen or an aromatic carbocyclic radical optionally alkylated, alkoxylated, or halogenated; R desigmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,

tert-butyl, pentyl, isopeutyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, and like C H radicals wherein s is an integer amounting to less than 9. Illustrative of the aralkyl radicals occasionally *present are such as Of these at least 1 and as many as several .O-lower alkyl groupings replace hydrogen. Still further, Ph represents-in particular instances-a carboxyphenyl, nitrophenyl, or di(lower alkyl)phenyl radical.

Equivalent to the basic amines of this invention for the purposes described are non-toxic acid addition and quaternary ammonium salts thereof, the compositions of which may be symbolized by wherein Het, Ar, R, Alk, Alk, .n, m, and Ph have the meanings hereinbefore assigned; Q is selected from among hydrogen andlower alkyl, hydroxyflower'alkyl), and lower alkenyl radicals, as also such aralkyl radicals as benzyl, phenethyl, and naphthylmethyl; T is 1 equivalent of an anion-e-for example, chloride, bromide, iodide, nitrate, phosphate, sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate, toluenesulfonate, acetate, lactate, succinate, malate; maleate, tartrate, citrate, .gluconate, ascorbate, benzoate, cinnamate, or the like- -which, in combination with the cationic portion of a salt aforesaid, is neither pharmacologically nor otherwise undesirable in pharmaceutical dosage; and y is 1 except "where Ph comprises an amino radical, in which case y is either-l or 2.

The application for Letters Patent securing the invention herein described and claimed is a continuation-in-part of applicants priorcopending application, Serial No. 689,273, filed October 10, 1957, and now forfeited.

-:The compounds hereindisclosed are useful because of: their valuable pharmacological properties. Thus, for

example, the subject compositions are selective CNS- depressant, anorectic, spasmolytic, and fungicidal agents;

and especially theitrialkoxybenzoates of this invention As to the aromatic carbocyclic radicals designated by Ar in the structural formula, these are principally phenyl or naphthyl groupings which can comprise, in place of nuclear hydrogen, 1 or more straightor branched-chain alkyl or alkoxyradicals, or halogen, or combinationsof these substituents, the alkyl and alkoxy substituents ordinarily being of lower order, which is to say embracive of fewer than 9 carbon atoms.

The lower alkylene and alkenylene radicals represented by Alk and Alk' in the formula are bivalent acyclic straightor branched-chainhydrocarbon moieties, saturated or containing not more than 1 double bond, and typified by methylenejethylene, vinylene, trimethylene, propylene, 1,3-propenylene, tetramethylene, .Z-methyl-l, S-propenylene, and 2,2-dimethyl-LES-propylene groupings. It will be recognized that when n or min the formula is 0, the apposed term drops out; and when both It and m are 0, the compounds referred to can be depicted Het, Ar, R, and Ph being defined as before.

Pb in the formula unexceptionably depicts a substituted phenyl radical, as aforesaid, but the nature and number of the substituent groupings can vary within rather wide limits. Thus, Ph represents a halophenyl radicalas for example, chlorophenyl, dichlorophenyl, trichlorophenyl, and the 1ikean-d, alternatively, it represents an alkoxyphenyl radical-particularly, a (lower alkoxy)- phenyl radical, which is to say a phenyl radical wherein are characterized by an unexpectedly potent and diverse tranquilizing effect on the central nervous system.

The compounds to which this inventionmelates are pre parable by a variety of methods, but the preferred process proceeds via contact of a carbinol of the formula Het Ar-(l-Alkn-OH with an anhydride of the formula Het, Ar, R, Alk, Alk', n, m, and Ph being selected from the previously defined groups of radicals in accordance with the particular product sought to be prepared. An inerthydrocarbon solvent may be used, or not, as desired, except that where a tertiary hydroxyl is to be esterified, both the solvent and catalytic amounts of, for example, mineral acid or an acid salt such as zinc chloride, are advisably present. Solvents commonly but, in thecase of at least alcohols, unessentially employed are benzene,- toluene, xylene, and the like; and a variety of catalysts may be incorporated ad libitum (with the exception as to, tertiary carbinols above noted), for instance caustic,'alkali metal alkoxide, pyridine orother tertiary amine, sodium acetate, etc. Water is excluded. The process is generally carried out at elevated temperatures in comparatively short periods oftim e, 2-5 hours at -1 60? being representative. In addition to its more general applicability, this solvent of the carbinol 3 4 preferred procedure leads to products of greater purity and in higher yield.

Other means of manufacturing the claimed compositions include (1) transesterification in hot hydrocarbon I with, ordinarily, a lower alkanoate of the acid under the influence of an alkali metal alkoxide, alcoholic caustic, or a comparably basic substance, or an acid such as hydrogen chloride; (2) interaction of the carbinol aforesaid with an acid chloride Ph-Alk -C Cl generally without solvent, but alternatively in benzene,

toluene, xylene, or the like, and with anhydrous caustic, .alkali, or alkaline carbonate, pyridine or other tertiary base, or sodium hydride optionally present as an acid acceptor; and (3) interaction of the carbinol aforesaid with an acid Ph--Alk COOH in the presence of pyridine or equivalent solvent and' 'mediated by a hydrocarbonsulfonyl chloride, as for example, benzenesulfonyl chloride, toluenesulfonyl chloride, etc. The preparation from carbinol and acid chloride usually requires from 3 to 24 hours at temperatures ranging from 35 to 165, -1 to 6 hours at 100-140 being preferred where no Solvent or catalyst is employed.

.The claimed N-alkyl and N-aralkyl compositions are .derived from 4-benzoylpyridine, which is converted to the appropriate pyridinium compound by quaternization with a selected alkyl or aralkyl halide, the resultant pyridinium compound being catalytically hydrogenated tothe corresponding piperidinealkanol, and this material thereupon being esterified by one of .the procedures hereinbefore set forth. As variations on the foregoing preparative procedures, the N-oxido compounds hereof can be obtained by the action of an appropriate peracid on an ester of choice, as illustrated by'Example 21 hereinafter; and the alkoxycarbonyl esters of the invention can be derived from correspondingcarboxy compounds by esterification catalyzed with mineral acid (see Example 32). Commercially unavailable carbinol intermediates wherein the phenyl radical is alkylated or halogenated can be syn-, 1

thesized by combining the corresponding Grignard reagents Ph- -MgX QT a Q and T being limited by the meanings hereinbefore assigned, and it being additionally provided that Q is not hydrogen. Quaterniz-ation takes place in the temperaturerange between 45 and 100, using an inert solvent such as chloroform, acetone, butanone, methanol, butanol, or the like as reaction medium. Quaternization is ordinarily completed in from 1 to 48 hours and is generally carried out in a closed system if a lower alkyl halidesuch as methyl chloride-is one of the reagents. Using methyl bromide, the manufacture of quaternary ,with a suitable amino aldehyde in ethereal medium and,

salt may be smoothly effected in butanone solution at 70, the reaction time being approximately 1 hour.

' The following examplesdescribe in detail certain of the compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practicedwithout departing from the purpose and intent of this disclosure. In the examples hereinafter detailed, temperatures are given in degrees centigrade, pressures in millimeters of mercury or pounds per square inch (psi), and relative amounts of materials in parts by weight, except as otherwise noted. I

Example 1 at 130-150 for 11 hours under-nitrogen. The mixture is then cooled to about 30, at which point an excess of aqueous 10% caustic is introduced. The resulting mixture is thoroughly extracted with ether, and the ether extract in turn is extracted with dilute mur-iatic acid. The acid extract is made basic with lye, the resulting precipitate of aaphenyl-4-pyridineme1thyl o-chlorobenzoate being taken'up in ether. 'I hisether extract is dried over anhydrous potassium carbonate, filtered, and stripped of solvent by evaporation, fol-lowing which the residual oil is distilled in vacuo. The pale yellow fraction coming over at l-l9=5. under 0.15 mm. pressure is OL-P'heHYI-4-PYI- idinem'ethyl o-chlorobenzoate, of the formula I Cl Example 2 V Example 3 a Phenyl-2-pyridinenrethyl p-chlarobenzoata-Using essentially the technique set forth in Example 1, but substituting for the u-phenyl-4-pyridinemethanol and o-chlorobenzoyl chloride therein 37 parts of a-phenyI-Z-pyridinemethanol land 60 parts of p-chlorobenzoyl chloride, respectively, one obtains a-phenyI-Z-pyIidinemethyl pchlorobenzoate as a colorless sol-id melting at approximately 7 6-77 when recrystallized from petroleum ether. The product has the formula Example 4 A. 3,4,5-lrichlorbenzoz'c anhydride.-A solution consisting of 70 parts of thionyl chloride and 25 parts of 3,4,5striohlorobenzoic acid is heated at. the boilingpoint under reflux for 3 hours. Excess thionyl chloride is then removed by vacuum distillation, 'and-the'residual 3,4,5- trichlorobenzoyl chloride-is taken up in- 100 parts of-anhydrous ether. To this solution is added 25 parts of13,4,5 trichlorobenzoiclacid dissolved in 3 OOparts er anhydrous ether, followed cautiously and with agitation at room temperatures by 15 parts of pyridine. The desired 3,4,5-trichlorobenzoic anhydride precipitates almost instantly and is isolated by filtration. Digested with saturated aqueous sodium bicarbonate and then consecutively washed with water, methanol, and ether, the colorless product melts in the range 206-210".

B. a Phenyl-4-pyridinemethyl 3,4,5-trichl0r0benz0- ate.A mixture of 21 parts of 3,4,5-trichl0robenzoic anhydride, 9 parts of u-phenyl-4-pyridinemethanol, and 450 parts of xylene is heated to boiling and sufficient solvent distilled off to removeany traces of moisture present. Boiling is then maintained under reflux for approximately 6 hours, at which point the reaction mixture is filtered, and the filtrate thereupon washed with aqueous alkali. Solvent is evaporated under reduced pressures, affording as the residue a-phenyl-4-pyridinemethyl 3,4,5-triohlorobenzoate. The product has the formula C. 06 Phenyl-4-pyridinemethyl 3,4,5-trichl0robenzoate lzydrochloride.-An anhydrous ether solution of zit-phenyl- 4-pyridinemethyl 3,4,5-trichlorobenzoate is acidified with a slight excess of hydrogen chloride dissolved in absolute 2-propanol. The precipitate thrown down is recovered on a filter, washed thereon with ether, and finally dried in air. crystallized from a mixture of ethanol and ether, 4

the a-phenyl-4-pyridinemethyl 3,4,5-trichlorobenzoate hydrochloride 50 produced melts at 205-207".

Example cutting the reaction time to 2 hours, there is obtained zxphenyl-4-pyridinemethyl o methoxybenzoate, boiling in the range 180-215 under 0.8 pressure. The product has the formula f I O 1 a Q' i Q I $GH3 Example 6 a-Plzenyl-4-pyridinemethyl p-methoxybenzoate.-Using essentially the technique set forth in Example 5, but substituting 73 parts of p methoxybenzoyl chloride for the o-methoxybenzoyl chloride called for therein, there is obtained at pheuyl-4-pyridinen1ethyl p-methoxybenzoate, which boils in the range 185-205 at 0.3 mm. pressure. The product solidifies on standing and melts at 94-96". It has the formula mama 96-99". It has the formula i Example 8 m-Phenyl-4-pyridinemethyl lp-methoxyphenylac'etate.- Using essentiallythe technique set forthin Example 5, but substituting parts of p-methoxyphenylacetyl.ch10: ride for the o-methoxybenzoyl chloride therein, one Ohtains a-phenyl-4-pyridinemethyl p-methoxyphenylacetate, boiling in the-range -215 under 0.4 mm. pressure. The product has the formula. l

l O i i i @ono-iiorn-Q-oom Example 9 hydrochloride melts at 210-212 and has the formula 0 e011; Q-hno-ii-Q-oom i .HCI Example 10 A. a Phenyl-4-pyridinemethyl 3,4,5-trimeth0xybenz0- ate hydrochloride.A mixture of 45 parts of methyl 3,4,5 trimethoxybenzoate, 37 parts of a-iphenyl-4-pyridinemetha- 1101, and 2900 parts of anhydrous xylene in the presence of excess sodium is concentrated to volume bydistillation under a nitrogen atmosphere during j approximately 7 hours. From the reaction mixture, at room temperatures, is filtered a brown lgranular solid. 'Ilhefiltrate is diluted with 350 parts of anhydrous ether and then made acid with abare excess of hydrogenchloride dissolved in absolute, 2-propano1. The white precipitate which is thrown down is recoveredon a filter, washed thereon with ether, next washed by suspension in cold water, and finally dried inair at approxiniatelyjSOK This material is a-phenyl-4-. pyridinemethyl 3,4,5 -.trimethoxybenzoate hydrochloride, crystallizable from a mixture of ethanol. and anhydrous ether, and which melts at approximately 219-220. The product has the formula I OCH: ono-o-oom .1101

.OCHa

a Phenyl 4-pyr idinen ethyl 3,4,5-trirrtethoxybenz- Lll.- AI1 aqueous solution of a-phenyl-4-pyridinemethyl 3,4,5-trin1ethoxybenzoate hydrochloride is made alkaline.

Extraction of the resultant mixture with ether and drying of the ether extract'over anhydrous potassium carbonate,

1 this mixture inthe cold. Copious precipitation of the maleate occurs. The desired salt is isolated by filtration. It melts at 117-1 19 with gas evolution.

i Example 11 a-Phenyl-4-pyridinemethyl 2,3,4-trimethoxybenzoate hydrochloride.Using the technique of Example A, but substituting 45 parts of methyl 2,3,4-trirnethoxybenzoate for the methyl 3,4,5-trimethoxybenzoate therein, there is obtained a-phenyl-4-pyridinemethyl 2,3,4-trimethoxybenzoate hydrochloride, of the formula I (FCHa OCH:

Example 12 a-Pherjlyl-4-pyridinemethyl 2,4,6-trimethoxybenzoate hydrochloride.-Using the technique of Example 10A, but substituting 45 parts of methyl 2,4,6-trimethoxybenzoate for the methyl 3,4,5-trimethoxybenzoate therein, there is obtained a-phenyl-4-pyridinemethyl 2,4,6-trimethoxybenzoate hydrochloride, of the formula it -CHOG -OCH3 OCH3 Example 13 a-Phenyll-pyridz'nemethyl 3,4,5-trieth0xybenzoate hydr0chloride.A mixture of 55 parts of 3,4,5-triethoxybenzoyl chloride, 37 parts of a-phenyl-4-pyridinernethanol,

parts of triethylamine, and 1350' parts of anhydrous xylene is heated with agitation at the boiling point under reflux in an atmosphere of nitrogen for 22 hours." The mixture is then cooled, freed of precipitate by filtration, and made acid with hydrogen chloride dissolved in anhydrous 2-propanoL A second precipitate is thrown down, this material likewise being removed by filtration. The filtrate from this operation is stripped of solvent by evaporation, whereupon the residue is taken up in dilute aqueous muriatic acid. The resultant solution is washed with ether and then made alkaline, producing an oil-andfollowed byevaporation of the solvent, affords a-phenylwater mixture which is extracted with ether. The ether extract is dried over anhydrous sodium sulfate, treated with decolorizing charcoal, and finally evaporated-to a 'viscous dark brown oil. Distillation of the oil at 0.3 mm. pressure and 160 vapor temperature serves to remove 4-benzoylpyridine present as a hy-product. The residue is taken up in hot absolute ethanol, and the resultant solution is made acid with hydrogen chloride dissolved in absolute Z-propanol. Upon addition of anhydrous ether, a granular ivory precipitate is thrown down. This material is a-phenyl-4-pyrid-inemetliyl 3,4,5-triethoxybenzoate hydrochloride, the melting point of whichis202-204". The product has the formula (BCzHs Example 14 the filtrate thereupon washed with aqueous alkali. Solvent is evaporated under reduced pressures, afiording a solid residue which, recrystallized from 2-propano1, melts at -116. The pure white material thus obtained is a-phenyI-Z-pyridinemethyl 3,4,5-trimethoxybenzoate, of the formula O N I TCHO-l-Q- OCHa l OOH B. a-Phenyl-2-pyridinemethyl 3,4,5-trimethoxybenzoate hydrochloride-An anhydrous ether solution of phenyl- 2-pyridinemethyl 3,4,5-trime'thoxybenzoate is acidified with a slight excess of hydrogen chloride dissolved in absolute 2-propanol. The precipitate thrown down is recovered on a filter, washed thereon with ether, and finally dried in air.- crystallized from a mixture of ethanol and other, the a-phenyl-2-pyridinemethyl 3,4,5-trimethoxybenzoate hydrochloride so produced melts at 172,5174.

Example 15 OCHa l .1161 OCH;

Example 16 ,3-Phenyl-4-pyridineethyl 3,4,5 trimethoxybenzoate.- Using the technique of Example 14A, but substituting 10 parts of 8-pheny1-4pyridineethano1 [prepared according toTschitschibabin, J. pr-akt. Chem, 69, 315] for the aphenyl-Z-pyridinemethanol prescribed therein, one obtains fi-phenyl-4-pyridineethyl 3,4,5-trimethoxybenzoate, which has the formula i 'y-Phenyl-4-pyridinepr0pyl 3,4,5-trimethxybenz0ate.- Using essentially the technique of Example 14A, but substituting 11 parts of 'y-phenyl-4-pyridinepropano1 for the a-phenylQ-pyridinemethanol prescribed therein, one ob- 'tains -phenyl-4-pyridinepropyl 3,4,S-trirnethoxybenzoate,

of the formula OCHs l -oaomomoc com Example 1 8 a-Phenyl-4-pyridinemezhyl 3,4,5-trimethoxyphenylacetate hydrochloride-Using the technique of Example 10A, but substituting 47 parts of methyl 3,4,5-trimethoxyphenylacetate for the methyl 3,4,5-trimethoxybenzoate therein, one obtains a-phenyl-4-pyridinemethyl 3,4,5-trimethoxyphenylacetate hydrochloride, melting at approximately 182 (with gas evolution). The product has the Example 19 Cil a-Phenyll-pyridinemethyl 3-(3,4,5-trimethoxyphenyl)- pr0pi0nate.-Using essentially the, technique set forth in Example 1,- but substituting 52 parts of 3-(3,4,5-trimethoxyphenyl)propionyl chloride [prepared according to Slotta and Heller, Ber., 63, 3042 (1930)], for the o chlorobenzoyl chloride prescribed therein, one; obtains a-phenyl 4 pyridinemethyl 3-(3,4,5-trirnethoxyphenyl) propionate, of the formula OCH: l GHO-O omom- -0 on:

I OCHa Example 20 a-Phenyll-pyridinemethyl 3,4,5 trimethoxyainnamate hydrochloride-Using the technique of Example 10A, but substituting 51 parts of methyl 3,4,5-trirnethoxycinnamate for the methyl 3,4,5-trirnethoxybenzoate therein,

one obtains a-phenyl-4-pyridinernethyl 3,4,5-trimethoxycinnamate hydrochloride, which melts at approximately ZOO-201 (with gas evolution). The product has the formula /N i 0 on;

u CHO-C CH=GH 0on3 I CH3 Example 21 0on3 l Q-ono-o- OOH: .5011. Example 22 A. a-mTolyl-4-pyridinemethanoL-To a suspension of 243'parts of magnesium in 140 parts of anhydrous ether is added, with agitatioma solution of 171 parts of mbromotoluene in 560 parts of anhydrous ether. The resultant mixture is heated at the boiling point under reflux for one hour, whereupon a solution of 107 parts of pyridine-4-aldehyde in 140 parts of anhydrous ether is cautiously introduced. Boiling under reflux is maintained overnight, after which the reaction mixture is decomposed with saturated aqueous ammonium chloride. Extraction with dilute aqueous muriatic acid serves to remove the desired amino alcohol in the form of the hydrochloric acid salt, which is converted to the free base by alkalization with potassium carbonate. The a-mtolyl-4-pyridinernethanol thus thrown down is purified by recrystallization fnom benzene. The product melts at 147-150.

B. a m Tolyl 4 pyridinemethyl 3,4,5 trimethoxybenzoate hydrochloride-A mixture of 20 parts of a-m-tolyl-4-pyridinemethanol and 28 parts of 3,4,5-trimethoxybenzoyl chloride is heated with agitation at [for 3 /2 hoursunder nitrogen. The mixture is then cooled to about 60, at which point an excess of aqueous 10% caustic is introduced. The resulting mixture is thoroughly extracted with ether, and the ether extract in turn is extracted with dilute muriatic acid. This acid solution is made basic with potash, the resulting precipitate of mm-tolyl-4-pyridinemethyl 3,4,S--trime'thoxybenzoate being taken upin ether. To the ether extract is added a slight excess of hydrogen chloride dissolved in Z-propanol. The a=m-tolyl-4-pyridinemethyl- 3,4,5-trimethoxybenzoate hydrochloride which is thrown down is filtered 0E and further purified by recrystallization from a mixture of absolute ethanol and ether. The product melts at 200-202 and has the formula of 'm-bromochlorobenzene for a W U oorn (1H3 CHa .HCI Example23 a m Tolyl 4 pyridinem'ethyl 3,4,5-triethoxybenzoate hydrochloride-A mixture of parts of u-rn-tolyl- 4-pyridinernethanol, 22 parts of 3,4,5-triethoxybenzoyl chloride, and 8 parts of triethylamine in 900 parts of anhydrous xylene is heated at-the boiling point of the solwent under reflux in an atmosphere of nitrogen during 24 hours. The reaction mixture is then cooled to room temperatures and filtered. To the filtrate is added an excess of hydrogen chloride dissolved in 2-propanol.

Evaporation of solvent by vacuum. distillation leaves a residue which is taken up in hot benzene. Upon cooling of the benzene solution, there is precipitated a mixture of salts which is recovered by filtration and resolved by suspension in hot water. The material which remains lundissolved is the desired a-m-tolyl-4-pyridinemethyl 3,4,5-triethoxybenzoate hydrochloride which, recrystalliz'ed from absolute ethanol, melts at 207-210. The product has the formula I I O C 2H5 H I oHo-o -0om,

I I .1101 CH3 0 C 2H5 Example 24 A. at p Ethylphenyl 4 pyridinemethanoL-Using the technique of Example 22A, but substituting 184 parts of p bromoethylbenzene for the m-bromotoluene therein,

there is obtained a-p ethylphenyl-4-pyridinemethanol.

B. a p Ethylphenyl 4 pyridinemethyl 3,4,5 triethoxybertzoate hydrochl0=rid'e.Using the technique of Example 23, but substituting 16 parts of a-p-ethylphenyl- 4-pyridinemethanol for the ot-m-tolyl-4-pyridinemethano1 therein, there is obtained u-p-ethylphenyl-4-pyridinemethyl 3,4,5-triethoxybenzoate hydrochloride, of the ctormula I O C 2H6 Example 25 A. a -m Chlorophenyl 4 pyridinem'ethanoL-Using the technique of Example 2 2A, but substituting 192 parts the m-bromotoluene therein, there is obtained a m-chlorophenyl-4-pyridinemethanol. This material melts at 133-135".

B. a m Chlorophenyl 4 pyridinemethyl 3,4,5-trimethoxybenzoate hydr0chl0ride.-To a solution of 33 -parts of a-m-chlorophenyl-4-pyridinemethanol in 450 parts of anhydrous toluene is added, portionwise with agitation at ISO-90 under a nitrogen atmosphere, 4 parts of sodium hydride. Heating at the prescribed temperatures is continued for 1 hour, whereupon a solution of approximately 43 parts of 3,4,5-trimethoxybenzoyl chloride in 180 parts of anhydrous toluene is introduced during 10 minutes. fIhe resulting mixture is maintained at 80 overnight, at which point 16 parts of methanol is 12 cautiously added to destroy excess hydride. After being washed with sufii'cient dilute aqueous muriatic acid to remove unreacted amino alcohol, the mixture is dried over calcium sulfate and evaporated to dryness. The residue is extracted with hot benzene, from which on cooling a further amount of unreacted amino alcohol is precipitated. This is filtered 01f, and an excess of hydrogen chloride dissolved in 2-propanol is added to the hot filtrate. From the filtrate, on cooling, the desired u-mchlorophenyl 4 pyridinemethyl 3,4,5 trimethoxybenzoate hydrochloride precipitates. Recrystallized from absolute ethanol, the material melts at 204-2061 The product has the formula 0 CH3 -ono-o-oorn .HCI

' Example 26 oz o Chlorophenyl 4 pyridinemethyl 3,4,5 tricthoxybenzoate hydrochloride.-Using the technique of Example 25B, but substituting for the a-rnrohlorophenyl- 4-pyridinemethanol and 3,4,5-trimethoxybenzoyl chloride therein 33 parts of a-o-chlorophenyl-4-pyridinemethanol and 45 parts of 3,4,5-triethoxybenzoyl chloride, respectively, there is obtained a-o-chlorophenyl-4-pyridinemethyl 3,4,5-triethoxybenzoate hydrochloride, which has the formula i 002135 I? I I l .1201 Cl 0 CnHa Example 27 A. a-Phenyl-4-piperidinemethan0l.--A solution of parts of a-phenyl-4-pyridinemethanol in a mixture of 660 parts of acetic acid and 220 parts of water is agitated during 9 hours under 45 psi. of hydrogen in the presence of platinum oxide catalyst. Approximately 4 parts of the catalyst is incorporated at the start of the reduction, another 4 parts being introduced at the end of the first 3 hours. Temperatures rise to around 35 in process. When the uptake of hydrogen indicates that reduction is complete, hydrogenation is stopped, catalyst is filtered ad, and acetic acid is stripped from the filtrate by vacuum distillation. The residue is taken up in water, and the resultant solution made alkaline with caustic soda.

The solid precipitate thrown down is isolated by filtration i i C. a,- Phenyl 4 p iperidineniezhyl 3,4;5 t ri'meth- Example 28 A. 4-benz0yl-1-methylpyridinium iodide-A mixture of 18 parts of 4-benzoylpyridine and 30 parts of methyl iodide in 400 parts of water-washed chloroform is heated at the boiling point under reflux overnight. Solvent is then stripped in vacuo at elevated temperatures, leaving as a residue 4-benzoyl-l-methylpyridiniurn iodide.

B. 1 methyl cc phenyl 4 '--piperidinemethanol.-A

,mixture of, parts of -4-ben zoyl-l-methylpyridinium .iodide, lpart of platinum oxide, and 175 parts of absolute :ethanol is hydrogenated ;ur1der pressures ofthe order-of it .50 psi. until the uptake of hydrogen-gas is consistent with the reduction in prospect. Catalyst isthen filtered oft and the filtrate distilled to remove sol-vent: present The residue is .;1 methylphenyl-fi-piperidinemethanol .hydroiodide, which is converted to the correspondingrbase .by dissolution in water andineutralization of this solution with aqueous sodium bicarbonate The base 'is isolated by extraction into ether anddistillation of solvent from the ether extract. i i

C. 1 methyl a phenyl 4 zfrimethoxybenzoate.-A mixture of '21 parts of l-methyla-phenyl-4-piperidinernethanol, 23 parts of 3,4,5-trimethoxybenzoyl .chloride, and 165 parts of dry benzene is heated at the boiling point under reflux tor 24 hours,

then cooled andfiltered. The filtrate is thoroughly mixed with an excess of dilute aqueous muriatic -acid, following which the benzene phase is discarded and excess aqueous caustic sodaris stirredin. Sufiicient potassium carbonate to insure saturation is next incorporated; following which the mixture is extracted withfether. jEvaporation of. solvent from the etherextract aifords'as aI-residuethe desired 1rmethyl-u-phenyll piperidinemethyl. 3,4,5-trimethoxybenzoate, which hasthe formula r OCHa OCH;

'l-octylpyridiniurn iodide,-whiol1 is converted via;low;wpressu're hydrogenation in the presence ,ofplatinum .oXidecat- :alyst to -1-octyl:a-phenyl4epiperidinemethanol. This .ma-

p iperidinemetltyl 3,4,5-

14 Example A. 4-benzoyl-1-benzylpyridinium chloride.-A solution of 37'parts of 4-benzoylpyridine and 65 parts of benzyl chloride in 750 parts of chloroform is heated at the boiling point underreflux for 26 hours. The solvent is then evaporated by vacuum distillation, whereupon the residue is crystallized from butanone to give pure white 4-bcnzoyl-l-benzylpyri-dinium chloride, the 'melting point of which is approximately 193-11949. i

' B; 'J-benzyl-u-phertyl-piperidinemethanol hydrochlo- -ride.-A mixtureof 16 parts of 4-benzoyl-l-benzylpyridin'ium chloride, lpart of platinum oxide and 160.parts of absolute ethanol -is hy'clrogenated'under pressures of the Ol'dEI'LOf 50ip;s.i."-When.;the uptake of hydrogen indicatsthat lthe desired reduction. is achieved, "hydrogena- 'tion:is stopped andthereactionmixture is filtereditorernoves'catalyst; Stripping of solventtfrom.the filtrate by vacuum distillation leaves a light brown oil which solidifies to an ec ru crystalline solid on standing. This solid is recrystallized from a mixture ofabsolute ethanol and anhydrous ether to give a pure white material. melting at l90-193. The product thus obtained is l-benzyl-aphenyl-4piperidinemethanol hydrochloride.

C. 1-beh2yl-a-phen;yl-4-piperidinemethyl 3,4,5-trimethoxybenzoate hydr0br0mr'de.-A suspension of 25 parts of 1=benzyl-a-phenyl-4-piperidinemethanol hydrochloride in .200 parts of benzeneis thoroughly mixed with an. excess of dilute aqueous potassiumicarbonate. The benzene phase is then separated and dried by azeotropic distillation. .Ihewe'ight of benzene. present is adjusted to approximate .8 times that of amino alcohol, whereupon 19. parts of terial, initurn,"is .esterified with .3,4,5..'- trimethoxybenzoyl chloride; and there is thus obtained 1-octyl -phenyl-4- piperidinemethyl 3,4,5trimethoxybenzo'ate, of the formula 3,4, 5 -trimethoxybenzoyl chloridedissolved in 200 parts :of -benzene is incorporated. Themixtureis heated at thehoiling 3 point under reflux for 26 hours. Precipitatiou occurs within. afew 1 minutes. flhe reaction mixture i scooled and filtered and the filtrate is thoroughly mixed avithaan excess of dilute .aqueous;muriatic acid. .A, heavy w er-in b l siltisroi n da and. i 9 :t h with theaqueous ,phase is. made basic with caustic. soda. The'resultant niixture is. saturated with potassium carbonate and then extracted with ether. The ether extract is dried over anhydrous potassium carbonate and then filtered and evaporated. There remains a glass which is taken up in ether. The ether solution is filtered to remove small amountspfinsoluble flocculentmaterial, following which it is made acid with} alcoholic hydrogen bromide. The semi-solid hydrobromic acid salt which results is separated andkrecrystallized from a mixture of Example 31 a-phenyl-4-pyfidinemethyl 0 -carbOxybenz0ate.-Using essentially thetechnique of Example 14A,but. substituting for the 3,4,5-trimethoxybenzoic anhydride and rat-phenyl- 2-pyridinemethanol therein approximately 8 parts of .phthalic =a nhyd ride and-.9; parts .-,of ,bz-phenyl lepyridinemethanol, respeetively, there is obtained a-pheny-l 4 pyridinemethyl.orcarboxybenzoate, .which ,melts -at approximatly 201-202". The product has the formula v 7 Example 32 I V I a-Phenyl-4 pyridinemethyl o-methoxycarbonylbenzoate hydrochloride.--To a solution of 15 parts of hydrogen 'chloride and 200 parts of methanol is added 12 parts of u-phenyl-4-pyridinemethyl o-carboxybenzoate. The resultant mixture is heated at the boilingpoint under reflux 'for 2 hours, then concentratedto approximately 4 vol- -ume by vacuum distillation. Addition of ether to the warm residue precipitate u-phenyIA-pyridinemet hyl omethoxycarbonylbenzoate hydrochloride as a granular white solid, which melts at 9699. The product has the 'formula 1 C-OCHa Examp 33,

u-Phenyl-4 pyridinemethyl p-ethoxycarbbnylbenzoate. A mixturefof 37 parts of a-phenyl-4-pyridinemethanol, approximately 43 parts of p-ethoxycarbonylbenzoyl chloride, andSOO parts of pyridine is heated at the boiling point under reflux for'one hour. The pyridine is then 'removed by vacuum distillation, whereupon the residue is washed with aqueous 10% caustic andthen extracted with ether. The ether extract in turn is extracted with lrrol aqueous 5% muriatic 'acid. The acid extract is made alkaline, and the resultant mixture is extracted with ether. This ether extract is dried over anhydrous potassium carbonate and then 'strippedofsolvent -by distillation. The residual golden oil is a-phe'nyl-4-pyridineniethyl pethoxycarbonylbenzoate, of the formula Example 34 a-Phenyl-4-py'ridine methyl o-nitrobenzoata-To asuspension of 334 parts of o nitrobenzoic acid-in 4900 parts of pyridine at 15 is added 706parts of benzenesulfonyl chloride followed, portionwise over a 15-minute period, by 370 parts of a-phenyl-4-pyridinemethanol. The resultant mixture is maintained at 15 for 3 hours and then dumped into 30,000 parts of ice-water. The precipitated solids are filtered off and dissolved in chloroform. Ihe chloroform solution is washed with aqueous potash and the with .water until free of pyridine. The solvent is reacid called for therein, one obtains a-phenyl-4-pyr-idinemethyl p-nitrobenzoate, which is converted to the corresponding hydrochloric acid salt by dissolution in absolute ethanol and acidification with a slight excess of hydrogen chloride dissolved in absolute 2-propanol. The product is thrown out of solution as a granular white solid by introduction of anhydrous ether. a-Phenyl-4-pyridinemethyl p-nitrobenzoate hydrochloride melts at 224-227 and has the formula 7 Example 36 t -Plzenyl 4 pyridiriemethyl mdimethylaminobe nzoate.-A mixture of 36'parts of methyl m-dimethylaminobenzoate, 37 parts of ot-phenyl-4-pyridinemethanol, and 2900 parts of anhydrous xylene in the presenceof excess sodium is concentrated to /5 volume by-distillation under a nitrogen atmosphere during-approximately 7 hours. From the reaction mixture, at room temperature, is filtered a brown granular solid containing the excess sodium. The filtrate, upon distillation, affords a-pheny1-4- moved by vacuum distillation, leaving as the residue, a-

phenyl-4-pyridinemethyl o-nitrobenzoate.- The product has the formula i I a-Phenyl-4-pyridiltemethylt p-nitrobenzoate hydr'ochlo rida-Using thetechnique of Example 34, but substituting 334 parts of p-nitrobenzoic acid for the o-nitrobenzoic pyridinemethyl m-dimethylaminobenzoate as a golden oil'boiling at 200-210 under 0.2 mm. pressure. The product has the formula V i I o tyrant), "Q -Q Example 37 a-Phenyl-4-pyridinemethyl p-diethylamin0benz0ate.-

Using the technique of Example 36, butsubstituting approximately 42 parts of methyl p-diethylaminobenzoate for the methyl.m-dimethylaminobenzoate therein, one obtains a-phenyl-4-pyridinemethyl p-diethylaminobenzoate. The product has the formula Example 38 i 0 CH3 onzo-iioom 6 H01 Example 39 a,a-DiphnyM-pyridinemthyl 3,4,5-trimethoxybenzoate.-A solution of 26 parts of a,a-diphenyl-4-pynidinemethanol, 40 parts of 3,4,5-trimethoxybenzoic anhydride, and 1 part of concentrated sulfuric acid in 800 parts of dry xylene is heated at the boiling point under reflux for 9 hours. The solution is then cooled and filtered. The filtrate is Washed with aqueous caustic, then with water, and finally is dried over anhydrous sodium sulfate. The desired a,a-diphenyl-4-pyridinemethyl 3,4,5- trimethoxybenzoate is isolated from this solution by evaporation of solvent. The product, crystallized from 2-propanol, melts at approximately 1605-1615". It has the formula OCHa if horn What is claimed is: 1. A compound of the formula i n Ph-CH-Alkn-0C-Alk -Ph" wherein Pyr is selected from the group consisting of radicals of the formulas lower alkyl lower alkyl 18 All: and All: are each selected from the group consisting of radicals of the formulas separating the radicals attached thereto by fewer than 5 carbon atoms, x being representative of a positive integer less than 6; n and m are selected from the group consisting of 0 and the positive integer 1; and Ph" is selected from the group consisting of radicals of the formulas (Mower alkyl O-lower alkyl 4 l O-lowe r alkyl O-lower alkyl O-lower alkyl O-lower alkyl 2. A compound of the formula 3. u-Phenyl-4-pyridinemethyl 3,4,5-trichlorohenzoate. 4. A compound of the formula O-lower alkyl I (if O-lower alkyl C HO-O a O-lower alkyl 5. A compound of the formula OCH3 fi OCHa 19 Z '6. u-Pheny1-4-pyridinemethy1 3,4,5-trimethoxybenzoate. 13. A compound of the formula 7. A compound of theforrnula N W /N 5 (|)-l0wer alkyl 7 i O 0E3 @CHOP1 0-lower alkyl I E I lower alkyl 0 1 1 owerzl *y CH-l 1k 1 -0C- -OGH Q Ower a yene a 10 14. u-m-Tolyl-4-pyridinemethyl 3,4,5-trimethoxybenzo- 11 ate.

15. A compound of the formula V N wherein the lower alkylene radical contains fewer than 3 carbon atoms. A l5 8. v-Phenyl-4-pyridinepr0pyl 3,4,5-trimethoxybenzor yl ate. V H

9. A compound of the formula @--CHOC O-lower alkyl )-lower alkyl 1 /N 16. a-m-Chlorophenyl-4-pyridinemethyl 3,4,5-trimethoxybenzoate.

- OCH3 References Cited in the file of this patent ff UNITED STATES PATENTS g 31mm 00133 2,899,437 Shapiro et a1 Aug. 11', 1959 (I)CH3 2,907,764 Voegtli et a1. Oct. 6, 1959 FOREIGN PATENTS wherein the lower alkylene radical contains fewer than 920491 France 1947 3 carbon atoms. OTHER REFERENCES y -py y 3,4,5-trimeth0XyPheI1y1- Karrer: Organic Chemistry (4th Eng. ed.), page 222 acetate. (1950).

11. u-Phenyl-4-pyridinemethyl 3,4,5-trimethoxycinna- 35 Kharasch et al.: J. Org. Chem, volume 18, pages mate. 7 1051-4 (1953).

12. a-Phenyl-4-pyridinemethyl 3,4,5-trimethoxybenzo Boyer et al.: J. Am. Chem. Soc, volume 80, pages ate 'N-oxide. I 2741-3, June 1958. 

1. A COMPOUND OF THE FORMULA 